Uric acid is a poorly-soluble substance having a molecular weight of 168 and a dissociation constant (pKa value) of 5.75 and is present in the form of uric acid or a conjugate base (urate) thereof, depending on the pH, when it is in the body fluid. In human and many other primates, due to the functional absence of urate oxidase (uricase) in the liver, uric acid is the final metabolite in purine metabolism. About 70% of the uric acid in the body resulted from dietary intake or endogenous production is eliminated through urine via the kidney, and the remaining 30% is eliminated through stools via the intestinal tube.
GLUT9 belongs to the family of glucose transporters encoded by SLC2A9 (Solute carrier family 2, facilitated glucose transporter member 9) genes, which was cloned as a molecule expressed in kidney, liver, placenta and the like in human (Non-Patent Document 1). According to a series of subsequent reports, the genome-wide association analysis confirmed the correlation between mutations in this molecule and blood uric acid levels, and this molecule functioned as a high-affinity, high-capacity uric acid transporter (Non-Patent Documents 2 and 3). It has also been reported that GLUT9 has two isoforms (GLUT9S and GLUT9L) due to N-terminal intracellular portion splice, and both has the same uric acid transport activity (Non-Patent Documents 4 and 5). Moreover, it has become evident that depressed function of this molecule causes severe hypouricemia from the analysis of GLUT9 genetic variation family (Non-Patent Documents 6 and 7).
Uric acid transport kinetics in the kidney have been studied since early times. Thus, uric acid first passes through glomerular, and then undergoes two-way transport via transporter which is either reabsorption or secretion, and eventually about 90% of the amount of the uric acid which has passed through glomerular is reabsorbed. GLUT9 is, from the information mentioned above, considered to play the main role in the uric acid reabsorption in the kidney, and thus an important molecule that controls blood uric acid levels. Therefore, a GLUT9 inhibitor is expected to reduce blood uric acid levels and be effective for hyperuricemia and pathological conditions associated therewith.
In Japan, hyperuricemia is defined as a condition wherein serum uric acid level exceeds 7.0 mg/dL, based on the concentration of uric acid dissolved in blood (Non-Patent Document 8). Persistent hyperuricemia causes gouty arthritis or kidney damage (gouty kidney) resulted from deposition of urate crystals in tissues. A prolonged disease period in gouty arthritis cases results in granuloma formation such as gouty tophus which is primarily due to the urate.
Further, in the recent years, hyperuricemia has been recognized as a lifestyle disease, and there has been many reports suggesting that hyperuricemia is associated with various pathological conditions. Remedy of hyperuricemia can be a potential treatment and prophylaxis for those pathological condition. Pathological conditions listed below are generally known to be associated with hyperuricemia and are particularly suggested to have a relationship with high uric acid.
1) Chronic Kidney Disease (CKD)
Many epidemiological studies have shown that hyperuricemia is a risk factor for development of terminal kidney failure or CKD onset (Non-Patent Documents 9, 10 and 11), and there is a report of intervention trial involving use of uric acid lowering agents which observed a renoprotective effect (Non-Patent Document 12). It is also reported that gene polymorphism of GLUT9 is responsible for CKD onset (Non-Patent Document 13).
2) Hypertension
Many clinical studies have gradually convinced that hyperuricemia is closely associated with the onset of hypertension (Non-Patent Documents 14 and 15). Also, there are clinical results reporting that blood pressure has been decreased by treating hyperuricemia (Non-Patent Document 16).
3) Diabetes
In a meta-analysis which puts together multiple prospective clinical studies, hyperuricemia is reported as an independent risk factor for type 2 diabetes (Non-Patent Document 17). Also studies involving use of mice and cultured cells show that high concentration uric acid suppresses insulin secretion and induces insulin resistance (Non-Patent Documents 18 and 19).
4) Cardiac Disease (Cardiovascular Disease, Cardiac Failure, Atrial Fibrillation)
The blood uric acid level has been reported as an independent risk factor or cardiovascular events (Non-Patent Document 20). Besides the events, a study of correlations between the characteristics of coronary artery and uric acid using intravascular ultrasound (IVUS) shows that hyperuricemia is associated with plaque volume and calcified lesion (Non-Patent Document 21). Hyperuricemia is also observed in many patients with chronic cardiac failure. A Japanese epidemiological study conducted under the Japanese Cardiac Registry of Heart Failure in Cardiology (J-CARE-CARD) test demonstrated that cardiac failure patients with hyperuricemia had a significantly higher rate of all-cause death and cardiac death (Non-Patent Document 22). In the recent years, a complication of hyperuricemia and atrial fibrillation has been attracting attention. It has been reported that prevalence of atrial fibrillation increases according to the serum uric acid level, and prevalence of hyperuricemia with 8 mg/dL or greater is significantly higher than those of 6.9 mg/dL or less (Non-Patent Document 23).
5) Arteriosclerotic Disease
Frequency of hyperuricemia in patients with hypertriglyceridemia is as high as about 30%, which is reported to be closely related with hyperuricemia and hyperlipemia (Non-Patent Documents 24 and 25).
6) Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH)
NAFLD is associated with fatty liver and is a chronic hepatic disease of unknown cause which is commonly diagnosed in people who do not drink alcohol. Further, a pathological condition with a more progressed inflammation and fibrosis is called “NASH” which may cause hepatic cirrhosis and hepatoma. Many NAFLD patients have a complication with hyperuricemia, where the serum uric acid level is an independent risk factor for NAFLD. There is a meta-analysis result reporting that 1 mg/dL increase in the serum uric acid level increases the risk of NAFLD onset by 21% (Non-Patent Document 26).
7) Psoriasis
It has been long known that psoriasis patients generally have a higher uric acid level relative to healthy subjects, as seen in the report that hyperuricemia was observed in about half of psoriasis patients (Non-Patent Document 27). In addition, as it has been reported that risks of cardiovascular disease and kidney damage are significantly higher in psoriasis patients relative to healthy subjects, hyperuricemia may be a factor that plays a role in increasing these risks (Non-Patent Documents 28 and 29).
As described above, a GLUT9 inhibitor is considered to be an agent for the treatment or prophylaxis of pathological conditions that involve high blood uric acid levels; specifically, hyperuricemia, gout (for example, gouty arthritis, gouty kidney, and gouty tophus) and the like. Further, it is considered to have potential to be useful as an agent for the treatment or prophylaxis of pathological conditions which are generally known to have a complication with hyperuricemia and are particularly suggested to have association with high uric acid; specifically, chronic kidney disease (CKD), hypertension, diabetes, cardiac disease (for example, cardiovascular disease, cardiac failure, and atrial fibrillation), arteriosclerotic disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), psoriasis and the like.